Aug 23, 2017

Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides

Nature Biotechnology
Naoki IwamotoGregory L Verdine

Abstract

Whereas stereochemical purity in drugs has become the standard for small molecules, stereoisomeric mixtures containing as many as a half million components persist in antisense oligonucleotide (ASO) therapeutics because it has been feasible neither to separate the individual stereoisomers, nor to synthesize stereochemically pure ASOs. Here we report the development of a scalable synthetic process that yields therapeutic ASOs having high stereochemical and chemical purity. Using this method, we synthesized rationally designed stereopure components of mipomersen, a drug comprising 524,288 stereoisomers. We demonstrate that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs. We report that Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug. Further, we elucidated a triplet stereochemical code in the stereopure ASOs, 3'-SpSpRp, that promotes target RNA cleavage by RNase H1 in vitro and provides a more durable response in mice than stereorandom ASOs.

Mentioned in this Paper

Molecular Stereochemistry
Phosphorothioate
Stereoisomers
Ribonuclease H1
Mipomersen sodium
Antistreptolysin O
RpIII toxin (Radianthus)
Triplet, Centriole
Phosphorothioate Oligonucleotides
RNA Cleavage

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